Silver-Catalyzed Anti-Markovnikov Hydroxyfluorination of Styrenes

Article abstract of DOI:10.1021/acscatal.6b03529

A silver-catalyzed radical hydroxyfluorination of styrenes with Selectfluor and H₂O has been explored with exclusive anti-Markovnikov-type regioselectivity, thus affording vicinal fluorohydrins with regioselectivities opposite that of noncatalyzed processes. This reaction is operationally simple, scalable under mild conditions. The mechanism studies and DFT calculations revealed that the reaction go through a radical mechanism.

Full text of DOI:10.1021/acscatal.6b03529

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Letter
Silver-Catalyzed Anti-Markovnikov Hydroxyfluorination of Styrenes
Yan Li, Xiaohuan Jiang, Chaoyue Zhao, Xiaoning Fu, Xiufang Xu, and Pingping Tang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03529 • Publication Date (Web): 25 Jan 2017
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Silver-Catalyzed Anti-Markovnikov Hydroxyfluorination of
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Yan Li,† Xiaohuan Jiang,† Chaoyue Zhao,‡ Xiaoning Fu,‡ Xiufang Xu*,‡ and Pingping Tang*,†,§
†State Key Laboratory and Institute of Elemento-Organic Chemistry and ‡Department of Chemistry, Nankai University,
Tianjin 300071, China
§Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300071, China
KEYWORDS silver-catalyzed radical hydroxyfluorination anti-Markovnikov-type fluorohydrins
Supporting Information Placeholder
ABSTRACT: A silver-catalyzed radical hydroxyfluorination of styrenes with Selectfluor and H2O has been explored with exclusive anti-
Markovnikov-type regioselectivity, thus affording vicinal fluorohydrins with regioselectivities opposite that of noncatalyzed processes.
This reaction is operationally simple, scalable under mild conditions. The mechanism studies and DFT calculations revealed that the reac-
tion go through a radical mechanism
.
Fluorinated organic compounds are important in pharma-
ceuticals, agrochemicals, and materials science.1 Among them,
vicinal fluorohydrins become a subject of particular interest
since they act as important precursors in the synthesis of bio-
logically active analogues of natural products,2 and an array of
versatile methods have been developed for the generation of
such compounds.3 But to our best knowledge, no anti-
Markovnikov-type hydroxyfluorination of styrenes has been
described. Herein, we reported a first example of silver-
catalyzed radical hydroxyfluorination of styrenes with Select-
fluor and H2O under mild reaction conditions, with exclusive
anti-Markovnikov-type regioselectivity, which affording vici-
nal fluorohydrins with regioselectivities opposite that of non-
catalyzed processes.
Table 1. Screening of hydroxyfluorination conditions
Fluorinating
entry
Ag salt
Additiveb
Yield(%)c
reagenta
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
NFSI
1
2
none
AgNO3
AgO2CPh
Ag2CO3
AgF
none
none
0
69
67
69
72
71
70
72
72
77
60
75
74
80
85
0
3
none
4
none
5
none
Traditional methods for the synthesis of vicinal fluorohy-
drins includes reduction of α-fluoro carbonyl compounds,4 and
ring opening of epoxides with hydrofluorination reagents,5 but
substrates for these reactions usually require several steps syn-
thesis with the use of some hazardous or toxic chemicals. The
straightforward methods to synthesis of vicinal fluorohydrins
were hydroxyfluorination of olefins.6 For example, Appelman
and co-workers reported an addition of hypofluorous acid to
alkenes to yield vicinal fluorohydrins.7 However, hypofluor-
ous acid is a volatile compound and thermally unstable. Re-
cently, new electrophilic fluorinating reagents such as Select-
fluor, NFSI, and Accufluor were used for selective hy-
droxyfluorination of alkenes with Markovnikov-type regiose-
lectivity.8 In addition, Toste and coworkers reported a chiral
phosphoric acid catalyzed the asymmetric hydroxyfluorination
of enamides.9 Despite the development of these methods, hy-
droxyfluorination of styrenes with anti-Markovnikov-type
regioselectivity has not been reported so far. The development
of a straightforward method to synthesis of vicinal fluorohy-
drins through the hydroxyfluorination of styrenes with anti-
Markovnikov-type regioselectivity is highly desirable.
6
Ag2SO4
AgSbF6
AgBF4
Ag2O
none
7
none
8
none
9
none
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16
17
18
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
none
none
ZnO
Zn(OTf)2
NaOTf
In(OTf)3
Sm(OTf)3
Sm(OTf)3
Sm(OTf)3
Sm(OTf)3
AgOTf
AgOTf
0
Me3NFPYBF4
0
a) 2.0 equiv of fluorinating reagent was used. b) 0.30 equiv of
additive was used. c) Yields were determined by H NMR with
benzyl chloride as a standard.
1
conditions (Table1, see the supporting information for more
details). When 1a was treated with Selectfluor in
PhNO2/H2O/CH3NO2 (v/v/v = 2.6/1/0.4) without any catalyst,
We began our investigations with employing 4-
fluorostyrene (1a) as the substrate to optimize the reaction
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Table 2. Scope of the silver-catalyzed hydroxyfluorination of styrenesa
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a) Reaction conditions: styrene 1 (1.0 equiv), AgOTf (10 mol%), Sm(OTf)3 (0.30 equiv), Selectfluor (2.0 equiv), PhNO2/H2O/CH3NO2
(v/v/v = 2.6/1/0.4), 30 °C, N2. Yields refer to isolated product. b) Reaction conditions: styrene 1 (1.0 equiv), AgOTf (10 mol%), Selectfluor
(2.0 equiv), (n-Bu)4NHSO4 (2.5 equiv), H2SO4 (1.0 equiv), PhNO2/H2O (v/v = 3/1), 50 °C, N2. c) SDS (20 mol%) was used instead of
Sm(OTf)3. SDS = Sodium dodecyl sulfate.
as reaction solvent was not clear. After thoroughly optimizing
the reaction conditions, reactions with 10 mol% of AgOTf, 2.0
equiv of Selectfluor and 0.30 equiv of Sm(OTf)3 in the
PhNO2/H2O/CH3NO2 (v/v/v = 2.6/1/0.4) under a N2 atmos-
phere were found to produce high yields of the desired product.
no desired product 2b was observed (Table 1，entry 1). To
our delight, we obtained the fluorohydrin 2b in 69% yield
when AgNO3 was used as the catalyst (Table 1, entry 2). En-
couraged by this initial result, we further evaluated the differ-
ent silver salts and AgOTf was found to be superior (Table 1,
entries 3-10). Subsequently, the introduction of additives (0.30
equiv) was investigated and Sm(OTf)3 was found to be the
most effective (Table 1, entries 11-15). No product was de-
tected in the presence of Sm(OTf)3 without AgOTf (Table 1,
entry 16). Further, Selectfluor emerged as the most suitable
fluorinating reagent and no desired product 2b was observed
when N-fluorobis(benzenesulfonyl)imide (NFSI) and N-
With the optimal conditions in hand, we explored the scope
and limitations of the hydroxyfluorination reaction (Table 2).
A variety of styrenes bearing an electron-donating or electron-
withdrawing group underwent the hydroxyfluorination to form
the corresponding fluorohydrins with isolated yields ranging
from 41% to 85%. The mild reaction conditions were compat-
ible with a number of functional groups including ketone, ester,
amide, nitrile, nitro, sulfonyl, chloro, bromo, even iodo sub-
stituents. The reaction of substrates 1g-1i, 1q containing elec-
tron-withdrawing groups exhibited slightly lower reactivity
and the different reaction conditions were used. With substrate
(1q), the cyclization product 2q was obtained in 62% yield.
Notably, the reaction was highly regioselective affording anti-
Markovnikov-type hydroxyfluorination products. These re-
fluoro-2,4,6-trimethylpyridinium
tetrafluoroborate
(Me3NFPYBF4) were used (Table 1, entries 17-18). The reac-
tion was carried out under a N2 atmosphere. In contrast, yield
was greatly diminished (5% yield) when the reaction was per-
formed under air. In addition, the reaction temperature was
important parameter, with hydroxyfluorination best performed
at 30 °C. The role of the combined use of PhNO2 and MeNO2
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sults further expanded the substrates scope of the reaction for
corresponding product [18O]2q was observed in the presence
of H218O, which confirmed that the hydroxyl group in the
product came from H2O.
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complex small molecules (1t, 1u) with moderate yields. It is
worth mentioning that the reaction time varied with each sub-
strate because fluorohydrins 2 decomposed slightly under re-
action conditions. Finally, to showcase the scalability and the
practicality of this hydroxyfluorination method, we performed
a gram-scale reaction using 4-bromostyrene (1c) as the sub-
strate under the standard reaction conditions, and fluorohydrin
2c was obtained in 72% isolated yield. The limitation of this
method was that there’s no reactivity for the hydroxyfluorina-
tion reaction of more electron-rich styrenes and unactivated
olefins, such as 4-methoxylstyrene and 1-tridecene.
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Figure 2. Gibbs free energy profiles for the silver-catalyzed radi-
cal hydroxyfluorination of styrene with Selectfluor and H2O. En-
ergies
are
calculated
using
B3LYP/SDD-6-
311+G(d,p)/SMD(PhNO2/H2O/CH3NO2 (v/v/v = 2.6/1/0.4))
To further understand the details of the mechanism, we per-
formed density functional theory (DFT) calculations for the
proposed mechanism (Figure 1B), taking styrene (1f) as the
―
model substrate. Our DFT calculation shows that loss of BF4
ion from Selectfluor in solution is thermodynamically favora-
ble because for this process the Gibbs free energy decreases by
2.7 kcal/mol. In addition, the electrospray ionization mass
spectrum of the Selectfluor solution shows that the cation (m/z
267) is the major species due to the loss of BF4―.11 Therefore,
we have used the cation (SF, as shown in Figure 1B) as an
alternative to the Selectfluor in the calculation. Because the
coordination of H2O to the naked Ag(I) ion is thermodynami-
cally favorable by -0.5 kcal/mol, (H2O)Ag(I) should act as the
active catalyst entering the catalytic cycle, as adopted in the
DFT study of the mechanism of silver-catalyzed decarboxyla-
tive fluorination by Zhang.12 As shown in Figure 2, firstly,
(H2O)Ag(I) coordinates with styrene and to form the complex
cpx1. This process is exothermic by 3.3 kcal/mol. Then cpx1
is oxidized by Selectfluor (SF) to produce Ag(II) intermediate
cpx2 and TEDA radical cation (pathway a in Figure 2A). In-
terestingly, in the presence of Sm(OTf)3, this step requires free
energy of activation of 13.3 kcal/mol, which is lower than that
without Sm(OTf)3 by 17.0 kcal/mol. This is because Sm(OTf)3
can stabilize the F―, which is formed during this oxidation
Figure 1. (A) Mechanism study. (B) Proposed Mechanism
Although the mechanistic details of this hydroxyfluorination
reaction are not clear, some preliminary mechanistic studies
were conducted. No desired fluorinated product was formed
when 1.0 equiv of the radical inhibitor butylated hydroxytolu-
ene (BHT) was added. When 2.0 equiv of N-
hydroxyphthalimide (NHPI) was added, the product 3 was
obtained in 16% yield determined by 1H NMR analysis of the
crude product (Figure 1A). In addition, much higher yields
were observed in the strict absence of O2 than in its presence.10
Together, these observations indicated that a radical chain
mechanism or single-electron transfer (SET) may be involved
in this transformation. In addition, the corresponding product
[18O]2e was observed in the presence of H218O, with 96% 18O
incorporation at the position indicated (Figure 1A), and the
process, by ligand exchange with OTf― to form the more sta-
ble SmF3, and thus promotes this oxidation step. Subsequently,
the Ag(II) intermediate cpx2 oxidizes the ligated styrene to
afford styrene radical cation, and the (H2O)Ag(II) is reduced
to (H2O)Ag(I) to complete the catalytic cycle. This redox pro-
cess is exothermic by 6.5 kcal/mol. Then, coupled with the
OTf―,the styrene radical cation reacts with H2O to generate the
benzylic radical intermediate, which abstracts fluorine from
Selecfluor (SF) to yield the final product and TEDA radical
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(2) (a) Wilkinson, J. A. Chem. Rev. 1992, 92, 505–519. (b) Huryn, D.
cation. The two steps are totally exothermic by 27.0 kcal/mol
(Figure 2B).
M.; Okabe, M. Chem. Rev. 1992, 92, 1745–1768. (c) Myers, A. G.;
Barbay, J. K.; Zhong, B. J. Am. Chem. Soc. 2001, 123, 7207–7219.
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Fluorine Chem. 2004, 125, 875–895.
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It is worthwhile to note that once the reaction occurs along
pathway a, the TEDA radical cation should be obtained. Then
TEDA radical cation can also oxidize the Ag(I) complex cpx1
to continue the catalytic cycle (pathway b in Figure 2A). Sig-
nificantly, the oxidation of cpx1 by TEDA radical cation re-
quires 5.8 kcal/mol less energy barrier than the oxidation of
cpx1 by Selecfluor (SF), which suggests that the catalytic
cycle should prefer to continue along pathway b after it starts
along pathway a. We have also considered other possible
pathways to afford Ag(II) and Ag(III) species.13 However,
these pathways are ruled out from the favored pathways be-
cause reactions along these pathways need to absorb additional
energies relative to pathways a and b (see Scheme S1 in the
supporting information).
(4) For select examples, see: (a) Kitazume, T.; Nakayama, Y. J. Org.
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In summary, we have developed a novel silver-catalyzed
radical hydroxyfluorination reaction of styrenes with Select-
fluor and H2O, providing rapid and efficient access to vicinal
fluorohydrins with exclusive anti-Markovnikov-type regiose-
lectivity for the first time. The reaction proceeds under mild
conditions with good functional group tolerance, which can be
further used for the hydroxyfluorination of complex small
molecules. Mechanistic investigations and DFT calculations
indicated that a radical mechanism may be involved in this
transformation. We anticipate that this mild silver-catalyzed
hydroxyfluorination method will find application in the syn-
thesis of fluorinated molecules in the pharmaceuticals, agro-
chemicals and materials.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization of all new com-
1
pounds including H, 13C and 19F NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(8) (a) DesMarteau, D. D.; Xu, Z.; Witz, M. J. Org. Chem. 1992, 57,
629–635. (b) Stavber, S.; Sotler-Pecan, T.; Zupan, M. Tetrahedron Lett.
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M.; Stavber, S. Org. Lett. 2004, 6, 4973–4976. (e) Kumar, A.; Singh, T.
V.; Venugopalan, P. J. Fluorine Chem. 2013, 150, 72–77.
ptang@nankai.edu.cn
xxfang@nankai.edu.cn
Notes
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Int. Ed. 2012, 51, 9684–9688.
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3877–3880.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the State Key Laboratory of Ele-
mento-organic Chemistry for generous start-up financial support.
This work was supported by National Program on Key Research
Project (2016YFA0602900) and the Natural Science Foundation
of China (21402098, 21421062, 21522205).
(12) Zhang, X. Comput. Theor. Chem. 2016, 1082, 11–20.
(13) (a) Yin, F.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134,
10401–10401. (b) Li, Z.; Song, L.; Li, C. J. Am. Chem. Soc. 2013, 135,
4640-4643. (c) Zhang, C.; Li, Z.; Zhu, L.; Yu, L.; Wang, Z.; Li, C. J. Am.
Chem. Soc. 2013, 135, 14082–14085. (d) Li, Z.; Wang, Z.; Zhu, L.; Tan,
X.; Li, C. J. Am. Chem. Soc. 2014, 136, 16439–16443. (e) Zhu, L.; Chen,
H.; Wang, Z.; Li, C. Org. Chem. Front. 2014, 1, 1299–1305. (f) Liu, Y.;
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Patel, N. R.; Flowersll, R. A. J. Org. Chem. 2015, 80, 5834–5841. (h)
Chen, H.; Zhu, L.; Li, C. Org. Chem. Front. 2017, DOI:
10.1039/C6QO00854B.
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56
57
58
59
60
361x411mm (300 x 300 DPI)
ACS Paragon Plus Environment